| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J Thorac Cardiovasc Surg 1997;114:676-678
© 1997 Mosby, Inc.
BRIEF COMMUNICATIONS |
Munich, Germany
Received for publication Dec. 23, 1996 accepted for publication March 12, 1997. Address for reprints: Joachim Weipert, MD, Klinik für Herz- und Gefäßchirurgie, Deutsches Herzzentrum München, Lazarettstr. 36, 80636 München, Germany.
The protease inhibitor aprotinin (Trasylol, Bayer AG, Leverkusen, Germany) is used in cardiac operations for acquired heart disease to reduce postoperative bleeding and allogeneic blood requirement.
1 Aprotinin is a polybasic polypeptide derived from bovine lung, and antibody production in human beings is likely to occur. Recently, deaths resulting from anaphylactic reactions after systemic aprotinin exposure in cardiac operations have been reported. 2 However, it is unknown by which pathway these reactions are mediated. Because the use of aprotinin at initial cardiac operations is widespread, at least in Europe, the risk for anaphylactic reactions at aprotinin reexposure may be increased. To study parameters to assess patients' individual risks for adverse reactions to aprotinin, we followed the course of aprotinin-specific antibodies of the immunoglobulin (IG) G class for 4 years.
With institutional approval and after informed consent, 36 consecutive adult patients having cardiac operations could be followed up. Only patients with no previous exposure to aprotinin were selected for this study. Blood specimens were drawn for the first time during their postoperative hospital stay or on an outpatient basis, but within 4 months after the operation. Four years later these patients were reinvestigated. Aprotinin was used according to the following protocol: A test dose of 10,000 KIU of aprotinin (1 ml) was given 10 minutes before the first bolus. Patients received an initial bolus of 2 x 106 KIU of aprotinin with the start of the operation, followed by an infusion of 5 x 105 KIU/hr. Additionally, 2 x 106 KIU of aprotinin was added to the pump prime.
By means of a semiquantitative, indirect enzyme-linked immunoassay (ELISA) test, the course of aprotinin-specific IgG antibodies was studied. In brief, ELISA plates were coated with aprotinin and incubated during 24 hours at 4° C. The plates were washed thereafter. Test specimens were serially diluted (1:2n) and added to the wells. A positive sample with a serial dilution of 1:10 to 1:1200 was used to establish a semiquantitative standard curve. After an incubation time of 2 hours at 37° C, the plates were washed again to remove unbound material. Then peroxidase-conjugated goat antihuman IgG antibodies were added and incubated for 3 hours at 37° C. After additional washings, substrate reaction was achieved with 2,2`-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) at 37° C and the absorbance was measured after 30 minutes at 405 nm. The amount of aprotinin antibodies was directly proportional to the colored product. Specific IgG antibody titers below a sample dilution of 1:20 were considered as being negative, between 1:20 to 1:50 as being questionable, and above 1:100 as certainly positive. Data are presented as mean ± standard deviation.
Twelve women and 24 men (median age 56 years, ranging from 33 to 67 years; coronary artery bypass grafting and valve operations) were studied. The final amount of aprotinin during extracorporeal circulation was 5.5 ± 0.79 x 106 KIU. The clinical course of all patients was uneventful, and patients were not reexposed to aprotinin. After a median time of 7 days (ranging from 6 to 122 days) after the operation, 17 patients had positive test results and 7 patients had questionably positive test results for IgG antibodies (Table I, A). At that time 12 patients had negative test results for IgG antibodies. After a median of 48 months (ranging from 44 to 51 months) after aprotinin exposure, 14 patients had positive blood samples and 10 patients had questionably positive blood samples for IgG antibodies. In 12 patients no IgG antibodies could be found. Also, an intraindividual change of the aprotinin-specific IgG antibody status from the first to the second investigation period could be observed (Table I, B). All patients with a change of the aprotinin-specific IgG status from negative to positive or questionably positive were tested for the first time within 6 to 9 days after aprotinin exposure. At both investigation periods, six (16.7%) patients had negative test results for aprotinin-specific IgG antibodies.
|
Aprotinin, a polybasic polypeptide, is a naturally occurring inhibitor of proteolytic enzymes and is derived from bovine lungs. The blood-saving effect after aprotinin application during cardiac operations with extracorporal circulation is well established. 1 As a xenogeneic protein it possesses antigenic properties, and for the cardiac surgical field the incidence of reported anaphylactic reactions at primary aprotinin exposition is between 0.5% and 1%. 3 Because of the increasing rate of reoperations in patients having heart surgery, reliable parameters for measuring the patient's individual risk for adverse reaction to aprotinin reexposure are desirable. Up to now it is unclear which parameter or test systems are able to predict the risk of allergic aprotinin reaction. To our knowledge, the multicenter study by Ruskowski and colleagues 4 involving 289 patients is the largest study so far. This study evaluated the immunologic sequel of aprotinin exposure up to 6 months after exposure in patients having cardiac operations. At that time the subcutaneous Prick test for aprotinin was positive in two patients only. The authors concluded that preoperative Prick testing at planned aprotinin reexposure might not be sensitive enough to predict the patient's risk of adverse aprotinin reaction. Aprotinin-specific IgG antibodies were found in 46% of the patients. However, the contribution for aprotinin-specific IgG antibodies to an allergic reaction to aprotinin is not yet established. 4
During the early period after aprotinin exposure, the percentage of patients (47%) with aprotinin-specific IgG antibodies in our study was nearly identical to the percentage reported by Ruskowski and coworkers. 4 As early as 7 days after aprotinin exposure, positive test results could be found. Four years after aprotinin exposure, all intraindividual shifts of the IgG test results from positive to negative and vice versa were found 
(Table I, B). Although we did not reexpose the patients to aprotinin at the second evaluation, one might speculate that patients with positive IgG status are still at risk for allergic reaction to aprotinin reexposure. This theory is supported by our clinical data. The overall risk for adverse reaction to aprotinin reexposure was 7 of 248 reexposures (2.8%) and the risk for adverse reaction was significantly higher within 4 months after aprotinin exposure as compared with late aprotinin reexposure (6.4% vs 1.9%). 3
Because of the documented blood-saving effect with aprotinin application in cardiac operations, reliable test systems are becoming an important issue of the comprehensive management of patients with reexposure to aprotinin. We found that 47% and 39% of the patients had positive test results for aprotinin-specific IgG antibodies early and late after exposition. Not much is known about the precise immunologic sequel during an adverse reaction to aprotinin. Determination of aprotinin-specific IgG antibodies might be a useful clinical indicator to identify individuals at risk for anaphylactic reactions to aprotinin, but more precise methods are desirable.
Footnotes
From the Clinic of Heart and Vascular Surgery, German Heart Center,a Division of Clinical Chemistry and Biochemistry in the Department of Surgery, Ludwig-Maximilians-University,b and Institute of Anesthesiology, German Heart Center,c Technical University of Munich, Munich, Germany. 
References
This article has been cited by other articles:
|
|
 |
|
  W. Dietrich, A. Ebell, R. Busley, and A.-L. Boulesteix Aprotinin and Anaphylaxis: Analysis of 12,403 Exposures to Aprotinin in Cardiac Surgery Ann. Thorac. Surg., October 1, 2007; 84(4): 1144 - 1150. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Beierlein, A. M. Scheule, W. Dietrich, and G. Ziemer Forty Years of Clinical Aprotinin Use: A Review of 124 Hypersensitivity Reactions Ann. Thorac. Surg., February 1, 2005; 79(2): 741 - 748. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Scheule, W. Beierlein, H. P. Wendel, M. J. Jurmann, F. S. Eckstein, and G. Ziemer APROTININ IN FIBRIN TISSUE ADHESIVES INDUCES SPECIFIC ANTIBODY RESPONSE AND INCREASES ANTIBODY RESPONSE OF HIGH-DOSE INTRAVENOUS APPLICATION J. Thorac. Cardiovasc. Surg., August 1, 1999; 118(2): 348 - 353. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Dietrich Incidence of Hypersensitivity Reactions Ann. Thorac. Surg., June 1, 1998; 65(90060): S60 - 64. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |
